Cardiotonic 3-methyl-4-(4-pyridinyl)benzeneamine compositions and method of use

ABSTRACT

3-Methyl-4-(4-pyridinyl)benzeneamines, useful as cardiotonic agents, are prepared by reaction of pyridine, benzoyl chloride and an appropriate 3-methyl-N,N-di-lower-alkylbenzeneamine in the presence of copper powder and decomposing the reaction mixture with alkali and, if desired, reacting a resulting 3-methyl-4-(4-pyridinyl)-N,N-di-lower-alkylbenzeneamine with hydrogen bromide and pyridine to obtain 3-methyl-4-(4-pyridinyl)benzeneamine.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to 3-methyl-4-(4-pyridinyl)benzeneamines, whichare useful as cardiotonic agents, to cardiotonic compositions containingthe same, a method of increasing cardiac contractility using the sameand to chemical processes for the preparation thereof.

(b) Description of the Prior Art

Koenigs et al., Ann., 509, 142-158 (1934) disclose, on pages 147-148,the preparation of 4-(4-pyridinyl)-N,N-dimethylbenzeneamine for which noutility is asserted. The compound is prepared by heating on a water batha mixture of 16 g. (0.202 mole) of pyridine with 14 g. (0.099 mole) ofbenzoyl chloride in the presence of 0.5 g. (0.0079 mole) of copperpowder and then treating the cooled reaction mixture with 12 q. (0.098mole) of N,N-dimethylbenzeneamine (i.e. N,N-dimethylaniline) followed byheating for five hours on a water bath, the ratio of pyridine to benzoylchloride to dimethylaniline to copper thus being 2:1:1:0.079. However ina section on pages 150-151 entitled (in translation) "CondensationProducts from m-Dimethylamino-toluene, Pyridine and Benzoyl Chloride",the authors describe a similar reaction using the same reactionconditions and precisely the same molar ratios of reactants, except that3-methyl-N,N-dimethylbenzeneamine (i.e. dimethyl-m-toluidine) was usedin place of the N,N-dimethylbenzeneamine used in the procedure describedon pages 147-148 of the reference. The product obtained is identifiedonly by its empirical formula, which corresponds, not to3-methyl-4-(4-pyridinyl)-N,N-dimethylbenzeneamine, which would result ifthe reaction followed the same course as the reaction usingN,N-dimethylbenzeneamine, but rather to a compound of unknowncomposition having the empirical formula C₂₁ H₂₁ N₂ OCl.

British Pat. No. 518,886 discloses 2-methyl-4-(4-pyridinyl)benzeneamine,useful as an intermediate for the preparation of dyestuffs, and Forsytheet al., J. Chem. Soc., 2921 (1926) disclose 4-(4-pyridinyl)benzeneamine,for which no utility is given.

SUMMARY OF THE INVENTION

In a composition of matter aspect, this invention relates to certain3-methyl-4-(4-pyridinyl)benzeneamines, which are useful as cardiotonicagents.

In a further composition aspect, the invention relates to cardiotoniccompositions for increasing cardiac contractility and containing, as theactive component thereof, a cardiotonically effective amount of a said3-methyl-4-(4-pyridinyl)benzeneamine.

In a method aspect, the invention relates to a method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering to such patient a medication containing, as theactive component, a cardiotonically effective amount of a3-methyl-4-(4-pyridinyl)benzeneamine.

In a process aspect, the invention relates to a process for preparing a3-methyl-4-(4-pyridinyl)-N,N-di-lower-alkylbenzeneamine which comprisesreacting pyridine, benzoyl chloride and a3-methyl-N,N-di-lower-alkylbenzeneamine in the presence of copper powderand decomposing the reaction mixture with alkali.

In a further process aspect, the invention relates to a process forpreparing 3-methyl-4-(4-pyridinyl)benzeneamine which comprises reactingpyridine, benzoyl chloride and a 3-methyl-N,N-di-lower-alkylbenzeneaminein the presence of copper powder, decomposing the reaction mixture withalkali and reacting the resulting3-methyl-4-(4-pyridinyl)-N,N-di-lower-alkylbenzeneamine with hydrogenbromide in the presence of pyridine.

In a still further process aspect, the invention relates to a processfor preparing 3-methyl-4-(4-pyridinyl)benzeneamine which comprisesheating a 3-methyl-4-(4-pyridinyl)-N,N-di-lower-alkylbenzeneamine withhydrogen bromide and pyridine.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically this invention relates to3-methyl-4-(4-pyridinyl)benzeneamines, which are useful as cardiotonicagents, having the formula: ##STR1## where R is hydrogen or lower-alkyl.

As used herein, the term lower-alkyl means saturated, monovalent,aliphatic radicals, including branched chain radicals of from one tothree carbon atoms, and thus represents methyl, ethyl, propyl andisopropyl.

The compounds of formula I where R is lower-alkyl are prepared byreacting pyridine, benzoyl chloride and a3-methyl-N,N-di-lower-alkylbenzeneamine in the presence of copperpowder, the molar ratio of pyridine to benzoyl chloride to thebenzeneamine derivative to copper powder being 1.5:1.5:1.0:0.03:, anddecomposing the reaction mixture with alkali according to the reaction:##STR2## where R is lower-alkyl. The reaction is carried out by heatingthe reactants on a steam bath, i.e. at a temperature from 90° to 95° C.,cooling to ambient temperature, and decomposing the reaction mixturewith alkali. Alternatively, the pyridine, benzoyl chloride and copperpowder are first heated on a steam bath, then treated with thebenzeneamine derivative, followed by further heating on a steam bath,and the mixture decomposed as before with alkali. The course of thereaction can be followed by thin layer chromatography.

These results are quite surprising, in view of the finding by Koenigs etal., Ann., 507, 142-158 (1934) who describe, at pages 147-148 of thereference, a similar reaction between pyridine, benzoyl chloride,N,N-dimethylbenzeneamine (i.e. N,N-dimethylaniline) and copper using thesame reaction conditions as described above except tha these earlierworkers used a molar ratio of pyridine to benzoyl chloride toN,N-dimethylbenzeneamine to copper powder of 2.0:1.0:1.0:0.079 tothereby obtain 4-(4-pyridinyl)-N,N-dimethylaniline, analogous to thecompounds of the instant invention where R is lower-alkyl. However, asdescribed at pages 150-151 of the Koenigs et al. publication, when thereaction was repeated using pyridine, benzoyl chloride,3-methyl-N,N-dimethylaniline and copper powder and employing preciselythe same reaction conditions and molar ratios of reactants as used inthe previously described preparation of4-(4-pyridinyl)-N,N-dimethylaniline, the reaction proceeded by anentirely different course and, instead of producing the expected3-methyl-4-(4-pyridinyl)-N,N-dimethylaniline, i.e. corresponding to acompound of formula I above where R is methyl, produced instead acompound of unknown composition, having the empirical formula C₂₁ H₂₁ N₂OCl, and presumably corresponding to a 1:1:1 adduct of pyridine, benzoylchloride and 3-methyl-N,N-dimethylaniline, which was then converted toits "free base". The latter is identified only by its empirical formula,C₂₁ H₂₀ N₂ O, and thus corresponds to a compound in which the precursorintermediate product has lost one molecule of hydrogen chloride.

The compound of formula I where R is hydrogen is prepared by heating acorresponding compound where R is lower-alkyl with aqueous hydrogenbromide and pyridine at a temperature from around 200° to 230° C. andisolating the product, in the form of the free base, from an alkalinemedium according to the reaction: ##STR3## where R is lower-alkyl.

Due to the presence of basic amino groups in the compounds of formula I,i.e. the 4-pyridinyl moiety and the 4-amino or4-(N,N-di-lower-alkylamino) group, the free base form represented byformula I above reacts with organic and inorganic acids to formacid-addition salts. The acid-addition salt forms are prepared from andorganic or inorganic acid. They are obtained in conventional fashion,for instance either by direct mixing of the base with acid or, when thisis not appropriate, by dissolving either or both the base and the acidseparately in water or an organic solvent and mixing the two solutions,or dissolving both the base and the acid together in a solvent. Theresulting acid-addition salt is isolated by filtration, if it isinsoluble in the reaction medium, or by evaporation of the reactionmedium to leave the acid-addition salt as a residue. The acid moietiesor anions in these salt forms are in themselves neither novel norcritical and therefore can be any acid anion or acid-like substancecapable of salt formation with the base.

Representative acids for the formation of the acid-addition saltsinclude formic acid, acetic acid, isobutyric acid,alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaricacid, succinic acid, succinamic acid, tannic acid, glutamic acid,tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid,glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin,benzoic acid, phthalic acid, salicylic acid, 3,5-dinitrobenzoic acid,anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid,3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid,3-indoleacetic acid, barbituric acid, sulfuric acid, methanesulfonicacid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid,p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid,acidic resins, hydrofluoro acid, hydrochloric acid, hydrobromic acid,hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoricacid, arsenic acid and the like.

All of the acid-addition salts are useful as sources of the free baseforms which are generated by reaction of the salts with an inorganicbase. It will thus be appreciated that if one or more of thecharacteristics such as solubility, molecular weight, physicalappearance, toxicity, or the like of a given base or acid addition saltthereof render that form unsuitable for the purpose at hand, it can bereadily converted to another, more suitable form. For pharmaceuticalpurposes, acid-addition salts of relatively non-toxicpharmaceutically-acceptable acids, for example hydrochloric acid, lacticacid, tartaric acid, methanesulfonic acid and the like are, of course,employed.

The compounds of formula I, and their acid-addition salts, have beenfound to be useful as cardiotonics. Their utility as cardiotonics wasestablished by their effectiveness in standard pharmacological testprocedures, for example in causing a significant increase in thecontractile force of the isolated cat atria and papillary muscle, thatis greater than 25% increase in papillary muscle force and right atrialforce, while causing only a lower percentage increase in right atrialrate (about one-third or less than the percentage increase in rightatrial or papillary muscle force), and also in causing a significantincrease in the cardiac contractile force in the anesthetized dog withlow or minimal changes in heart rate and blood pressure, that is, anincrease of greater than 25% in cardiac contractile force (or cardiaccontractility) and less than 25% change in heart rate and bloodpressure. The isolated cat atria and papillary muscle procedure and theanesthetized dog procedure are described in detail by Alousi et al.,Circ. Research, 45, 666-667 (1979).

The actual determination of the numerical pharmacological data for aparticular compound of the invention is readily obtained according tothe above-described standard test procedures by technicians versed inpharmacological test procedures without the need for any extensiveexperimentation.

In clinical practice, the compounds of formula I are normallyadministered orally or parenterally in a wide variety of dosage forms.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions canalso contain additional substances other than inert diluents, forexample lubricating agents such as magnesium stearate, talc and thelike.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art, such aswater and liquid paraffin. Besides inert diluents, such compositions canalso contain adjuvants, such as wetting and suspending agents, orsweetening, flavoring, perfuming and preserving agents. According tothis invention, the compounds for oral administration also includecapsules of absorbable material such as gelatin containing the activecomponent either with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thecompositions can also contain adjuvants such as stabilizing, preserving,wetting, emulsifying and dispersing agents.

They can be sterilized, for example by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions, by irradiation or by heating. They can also bemanufactured in the form of sterile solid compositions, which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentages of active component in such compositions may be variedso that a suitable dosage is obtained. The dosage administered to aparticular patient is variable, depending upon the clinician's judgmentusing as criteria: the route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component and the patient's response thereto. An effectivedosage amount of the active component can thus only be determined by theclinician after a consideration of all criteria and utilizing his bestjudgment on the patient's behalf.

The structures of the compounds of the invention were established by themode of synthesis, by elementary analyses and by ultraviolet, infraredand nuclear magnetic resonance spectra. The course of reactions wasfollowed, and the homogeneity of the products was ascertained, by thinlayer chromatography.

The manner and process of making and using the invention, and the bestmode contemplated by the inventors of carrying out the invention, willnow be described so as to enable any person skilled in the art to whichit pertains to make and use the same. The melting points areuncorrected.

EXAMPLE 1

A mixture of 320 g. (4.05 moles) of pyridine, 560 g. (3.98 moles) ofbenzoyl chloride, 365 g. (2.7 moles) of3-methyl-N,N-dimethylbenzeneamine and 5.0 g. (0.079 mole) of copperpowder was stirred and heated on a steam bath for ninety-eight hours andthen poured slowly with stirring into a solution of 500 ml. of 35%sodium hydroxide and 500 ml. of water. The mixture was stirred for onehour, cooled to ambient temperature and then extracted twice with 1liter portions of diethyl ether. The combined extracts were concentratedto dryness in vacuo and purified by chromatographic on 2.5 kg. of silicagel, eluting first with a 1:1 mixture of hexane: diethyl ether and thenwith a 2% solution of methanol in diethyl ether to give 65.2 g. of3-methyl-4-(4-pyridinyl)-N,N-dimethylbenzeneamine, m.p. 106°-109° C.

EXAMPLE 1A

It is contemplated that, by following a procedure similar to thatdescribed above in Example 1, substituting for the3-methyl-N,N-dimethylbenzeneamine used therein a molar equivalent amountof 3-methyl-N,N-diethylbenzeneamine, 3-methyl-N,N-dipropylbenzeneamine,or 3-methyl-N,N-diisopropylbenzeneamine, there can be obtained,respectively, 3-methyl-4-(4-pyridinyl)-N,N-diethylbenzeneamine,3-methyl-4-(4-pyridinyl)-N,N-dipropylbenzeneamine or3-methyl-4-(4-pyridinyl)-N,N-diisopropylbenzeneamine.

EXAMPLE 2

To a stirred solution of 48% hydrogen bromide was added, in smallportions over about a twenty minute period, 112 g. (0.53 mole) of3-methyl-4-(4-pyridinyl)-N,N-dimethylbenzeneamine. The mixture was thentreated dropwise with 470 ml of pyridine. The resulting solution wasthen slowly heated to 210°-215° C. while water was allowed to distilloff. The resulting melt was heated at 210°-215° C. for ten hours, thencooled and rendered basic by the addition of 35% aqueous sodiumhydroxide. The yellow solid which separated was collected, washed withwater and dried to give 60.8 g. of crude product which was set aside.The filtrate from the crude product was concentrated to dryness invacuo, and the residue was dissolved in 600 ml. of water and filtered.The insoluble material was combined with the original first crop to givea total of 67.8 g. of 3-methyl-4-(4-pyridinyl)-benzeneamine, m.p.121°-124° C.

EXAMPLE 2A

It is contemplated that by following a procedure similar to thatdescribed in Example 2 above, substituting for the3-methyl-4-(4-pyridinyl)-N,N-dimethylbenzeneamine used therein a molarequivalent amount of 3-methyl-4-(4-pyridinyl)-N,N-diethylbenzeneamine,3-methyl-4-(4-pyridinyl)-N,N-dipropylbenzeneamine or3-methyl-4-(4-pyridinyl)-N,N-diisopropylbenzeneamine, there can beobtained, in each case, 3-methyl-4-(4-pyridinyl)benzeneamine.

BIOLOGICAL TEST RESULTS

Utility of the compounds of formula I as cardiotonics was established bytest results obtained in the isolated cat atria and papillary muscleprocedure described above. Data so-obtained expressed in terms ofpercent change in right atrial rate (RAR), right artrial force (RAF) orpapillary muscle force (PMF) at dose levels expressed in terms ofmicrogram/ml. are given in the table below.

    ______________________________________                                        Dose    RAR         RAF         PMF                                           ______________________________________                                        Compound of Example 1                                                         10      22.7 ± 6.7                                                                             23.7 ± 8.7                                                                             13.2 ± 11.9                                30      48.7 ± 11.5                                                                            24.7 ± 8.8                                                                             50.8 ± 10.3                                100     33.7 ± 4.5                                                                             30.0 ± 10.0                                                                            55.2 ± 18.3                                Compound of Example 2                                                          1      -2.7 ± 2.7                                                                             0 ± 0    3.0 ± 3.0                                  10      7.3 ± 1.3                                                                              -14.7 ± 4.1                                                                            1.6 ± 6.9                                  30      91.6 ± 29.0                                                                            29.0 ± 2.6                                                                             73.0 ± 14.4                                100     124.7 ± 32.5                                                                           117.5 ± 39.6                                                                           244.2 ± 52.6                               ______________________________________                                    

We claim:
 1. The method for increasing cardiac contractility in apatient requiring such treatment which comprises administering orally orparenterally to such patient a medication in a solid or liquid dosageform containing, as the active component thereof, a cardiotonicallyeffective amount of a compound having the formula: ##STR4## where R ishydrogen or lower-alkyl or a pharmaceutically acceptale acid-additionsalt thereof.
 2. The method according to claim 1 wherein the cardiotonicis a 3-methyl-4-(4-pyridinyl)-N,N-di-lower-alkylbenzeneamine.
 3. Themethod according to claim 1 wherein the cardiotonic is3-methyl-4-(4pyridinyl)-N,N-dimethylbenzeneamine.
 4. The methodaccording to claim 2 wherein the cardiotonic is3methyl-4-(4-pyridinyl)-N,N-dimethylbenzeneamine.
 5. A cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically acceptable inert carrier and, as theactive component thereof, an effective amount of a compound having theformula: ##STR5## where R is hydrogen or a pharmaceutically acceptableacid-addition salt thereof.